Vascular diseases can cause premature deaths. These deaths can be prevented by knowing who is at risk for the disease. The studies proposed are to identify the genes that predispose individuals to a number of vascular diseases. PUBLIC HEALTH RELEVANCE: Thoracic aortic aneurysms leading to type A dissections (TAAD) are a significant cause of morbidity and mortality in the United States. We have established that up to 20% of patients with TAAD have a family history of the disease, indicating a genetic basis for the disease. TAAD is a genetically heterogeneous condition and we have mapped 4 loci for the condition and identified the defective gene at 2 of these loci, including TGFBR2, a receptor involved in TGF-2 signaling. We recently mapped a new TAAD locus using a large TAAD family that also had members with early onset coronary artery disease (CAD) and ischemic strokes (defined as onset less than 55 years of age), along with livedo reticularis (LR), a purplish rash resulting from occlusion of dermal capillaries. We determined that mutations in SMC 1-actin (ACTA2) were responsible for both the TAAD and, surprisingly, the occlusive disease of other arteries. We have also characterized families with MYH11 mutations, and affected members also had early CAD and LR. The aortic pathology associated with both ACTA2 and MYH11 mutations is characterized by loss of elastic fibers, increased proteoglycan, and regions of SMC loss;in addition, there were also areas of SMC hyperplasia and disarray. In addition, there was SMC hyperplasia causing occlusion of the vasa vasorum. These data lead to the hypothesis that mutations in genes encoding for other components of the SMC contractile and cytoskeleton complex lead to familial TAAD. In addition, the occlusive disease in patients with mutations in ACTA2 and MYH11 suggests that mutations in the SMC contractile genes may also cause premature stroke or CAD. We are in a unique position to test this hypothesis because of access to established resources, including the following: recruitment and characterization of a cohort of 378 families with TAAD;an established collaboration with the Baylor College of Medicine Human Genome Center (BCM-HGSC) for medical resequencing on a cost effective and high throughput platform;and access to the TexGen cohort of patients with non-familial TAAD, premature strokes and coronary artery disease. A medical resequencing project is proposed to test the hypothesis and identify genes that cause TAAD, CAD and early strokes.